Solution Thermodynamics of l-Glutamic Acid Polymorphs from Finite-Sized Molecular Dynamics Simulations

Abstract

Efficiently obtaining atomic-scale thermodynamic parameters characterizing crystallization from solution is key to developing the modeling strategies needed in the quest for digital design strategies for industrial crystallization processes. Based on the thermodynamics of crystal nucleation in confined solutions, we develop a simulation framework to efficiently estimate the solubility and surface tension of organic crystals in solution from a few unbiased molecular dynamics simulations at a reference temperature. We then show that such a result can be extended with minimal computational overhead to capture the solubility curve. This enables an efficient and self-consistent estimate of the solubility and limit of solution stability associated with crystal nucleation in molecular systems from equilibrium molecular dynamics without the need for sophisticated free energy calculations. We apply our analysis to investigate the relative thermodynamic stability and aqueous solubility of the α and β polymorphs of l-glutamic acid. Our analysis enables an efficient appraisal of emergent ensemble properties associated with the thermodynamics of nucleation from solutions against experimental data, demonstrating that while the absolute solubility is still far from being quantitatively captured by an off-the-shelf point charge transferable force field, the relative polymorphic stability and solubility obtained from finite temperature simulation are consistent with the experimentally available information on glutamic acid. We foresee the ability to efficiently obtain solubility information from a limited number of computational experiments as a critical component of high-throughput polymorph screenings.